IL-6 Blockade with Clazakizumab is Associated with Low Myeloid Cell Activation and Increased Type 2 Immune Responses in Non-survivors of COVID-19

BACKGROUND: IL-6 inhibitors have been associated with reduced mortality in severe COVID-19 in randomized clinical trials, but the comprehensive immunological impact of IL-6 blockade in the setting of an acute viral infection is poorly understood. METHODS: To gain insight into the systemic immune response to IL-6 inhibition in COVID-19, we utilized samples from patients who participated in a randomized placebo-controlled trial of clazakizumab, a direct anti-IL-6 monoclonal antibody, in severe COVID-19 in the pre-vaccine era. We applied multidimensional measurements of cytokines, chemokines, whole blood transcriptomes, and high-dimensional immune-metabolic flow cytometry to samples before and after treatment to study the changes in immune signatures after IL-6 blockade and to identify pathways associated with positive clinical outcomes. RESULTS: Clazakizumab was associated with a distinct myeloid activation signature and type 2 (T2) cytokine response. Non-survivors who received clazakizumab demonstrated a decoupling of these two clazakizumab-associated phenotypes, exhibiting the most pronounced T2 response coupled with less myeloid activation. Furthermore, elevated baseline levels of the emergency myelopoiesis related cytokine, IL-27, were strongly associated with non-survival after receipt of clazakizumab. CONCLUSIONS: These findings suggest that specific biomarkers may identify patients most likely to benefit from IL-6 blockade and could lead to more personalized applications in COVID-19 and other inflammatory conditions in which IL-6 targeted therapies are in use.